Medicine and Health Sciences Commons^™

Landscape Of Pharmacogenetic Variants Associated With Non-Insulin Antidiabetic Drugs In The Indian Population, Ambily Sivadas, S Sahana, Bani Jolly, Rahul C Bhoyar, Abhinav Jain, Disha Sharma, Mohamed Imran, Vigneshwar Senthivel, Mohit Kumar Divakar, Anushree Mishra, Arpita Mukhopadhyay, Greg Gibson, Km Venkat Narayan, Sridhar Sivasubbu, Vinod Scaria, Anura V Kurpad

Faculty, Staff and Student Publications

INTRODUCTION: Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India's distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants.

RESEARCH DESIGN AND METHODS: We mined 1029 Indian whole genomes for PGx variants, drug-drug interaction (DDI) and drug-drug-gene interactions (DDGI) associated with …

Author Correction: Hypomorphic Brca2 And Rad51c Double Mutant Mice Display Fanconi Anemia, Cancer And Polygenic Replication Stress, Karl-Heinz Tomaszowski, Sunetra Roy, Carolina Guerrero, Poojan Shukla, Caezaan Keshvani, Yue Chen, Martina Ott, Xiaogang Wu, Jianhua Zhang, Courtney D Dinardo, Detlev Schindler, Katharina Schlacher

Faculty, Staff and Student Publications

No abstract provided.

Incidence And Risk Factors Of Early Onset Vod/Sos Differ In Younger Vs Older Adults After Stem Cell Transplantation, Curtis Marcoux, Rima M Saliba, Whitney Wallis, Sajad Khazal, Dristhi Ragoonanan, Gabriela Rondon, Priti Tewari, Uday Popat, Betul Oran, Amanda Olson, Qaiser Bashir, Muzaffar Qazilbash, Amin Alousi, Chitra Hosing, Yago Nieto, Gheath Alatrash, David Marin, Katayoun Rezvani, Issa Khouri, Samer Srour, Richard Champlin, Elizabeth Shpall, Partow Kebriaei

Faculty, Staff and Student Publications

Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >25 years, with unique predictors …

A Biogeographical Appraisal Of The Threatened South East Africa Montane Archipelago Ecoregion, Julian Bayliss, Gabriela B Bittencourt-Silva, William R Branch, Carl Bruessow, Steve Collins, T Colin E Congdon, Werner Conradie, Michael Curran, Savel R Daniels, Iain Darbyshire, Harith Farooq, Lincoln Fishpool, Geoffrey Grantham, Zacharia Magombo, Hermenegildo Matimele, Ara Monadjem, Jose Monteiro, Jo Osborne, Justin Saunders, Paul Smith, Claire N Spottiswoode, Peter J Taylor, Jonathan Timberlake, Krystal A Tolley, Érica Tovela, Philip J Platts

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Recent biological surveys of ancient inselbergs in southern Malawi and northern Mozambique have led to the discovery and description of many species new to science, and overlapping centres of endemism across multiple taxa. Combining these endemic taxa with data on geology and climate, we propose the 'South East Africa Montane Archipelago' (SEAMA) as a distinct ecoregion of global biological importance. The ecoregion encompasses 30 granitic inselbergs reaching > 1000 m above sea level, hosting the largest (Mt Mabu) and smallest (Mt Lico) mid-elevation rainforests in southern Africa, as well as biologically unique montane grasslands. Endemic taxa include 127 plants, 45 vertebrates …

Evaluation Of Treatment Parameters For Focused-Extracorporeal Shock Wave Therapy In Knee Osteoarthritis Patients With Bone Marrow Lesions: A Pilot Study, Hani Al-Abbad, Jacqueline E Reznik, Erik Biros, Bruce Paulik, Rob Will, Samuel Gane, Penny Moss, Anthony Wright

Faculty, Staff and Student Publications

OBJECTIVES: To evaluate the effect of different dosage parameters of focused-extracorporeal shock wave therapy on pain and physical function in knee osteoarthritis patients with bone marrow lesions. In addition, to investigate pathophysiological changes based on imaging and biomarker measures.

METHODS: Using a single-case experimental design, a total of 12 participants were randomly allocated in 4 equal groups of 3 to receive different dosages of focused-extracorporeal shock wave therapy. Each group received either 4 or 6 sessions of 1500 or 3000 shocks over 4 or 6 weekly sessions. Participants underwent repeated measurements during the baseline, intervention, and post-intervention phases for Western …

Draft Genome Sequences Of Pseudomonas Strains Zfem001–005 Isolated From The Intestine Of Larval Zebrafish Danio Rerio, Sabona B Simbassa, Justin Clark, Keiko Salazar, Anthony Maresso, Anne-Marie Krachler

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Here, we report the draft genome sequences of Pseudomonas strains zfem001–005, five isolates from the intestinal microbiota of healthy larval zebrafish Danio rerio at a developmental age of 7 days post fertilization. The isolates have been identified as Pseudomonas sediminis, Pseudomonas japonica, Pseudomonas otitidis, Pseudomonas sichuanensis, and Pseudomonas tohonis, respectively.

Automating Data Analysis For Hydrogen/Deuterium Exchange Mass Spectrometry Using Data-Independent Acquisition Methodology, Frantisek Filandr, Vladimir Sarpe, Shaunak Raval, D Alex Crowder, Morgan F Khan, Pauline Douglas, Stephen Coales, Rosa Viner, Aleem Syed, John A Tainer, Susan P Lees-Miller, David C Schriemer

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We present a hydrogen/deuterium exchange workflow coupled to tandem mass spectrometry (HX-MS2) that supports the acquisition of peptide fragment ions alongside their peptide precursors. The approach enables true auto-curation of HX data by mining a rich set of deuterated fragments, generated by collisional-induced dissociation (CID), to simultaneously confirm the peptide ID and authenticate MS1-based deuteration calculations. The high redundancy provided by the fragments supports a confidence assessment of deuterium calculations using a combinatorial strategy. The approach requires data-independent acquisition (DIA) methods that are available on most MS platforms, making the switch to HX-MS2 straightforward. Importantly, we find that HX-DIA enables …

Immune Heterogeneity In Small-Cell Lung Cancer And Vulnerability To Immune Checkpoint Blockade, Barzin Y Nabet, Habib Hamidi, Myung Chang Lee, Romain Banchereau, Stefanie Morris, Leah Adler, Velimir Gayevskiy, Ahmed M Elhossiny, Minu K Srivastava, Namrata S Patil, Kiandra A Smith, Rajiv Jesudason, Caleb Chan, Patrick S Chang, Matthew Fernandez, Sandra Rost, Lisa M Mcginnis, Hartmut Koeppen, Carl M Gay, John D Minna, John V Heymach, Joseph M Chan, Charles M Rudin, Lauren A Byers, Stephen V Liu, Martin Reck, David S Shames

Faculty, Staff and Student Publications

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but …

Nanofibrous Multidomain Peptide Hydrogels Provide T Cells A 3d, Cytocompatible Environment For Cell Expansion And Antigen-Specific Killing, Viridiana Leyva-Aranda, Shailbala Singh, Maria J Telesforo, Simon Young, Cassian Yee, Jeffrey D Hartgerink

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T cells have the ability to recognize and kill specific target cells, giving therapies based on their potential for treating infection, diabetes, cancer, and other diseases. However, the advancement of T cell-based treatments has been hindered by difficulties in their ex vivo activation and expansion, the number of cells required for sustained in vivo levels, and preferential localization following systemic delivery. Biomaterials may help to overcome many of these challenges by providing a combined means of proliferation, antigen presentation, and cell localization upon delivery. In this work, we studied self-assembling Multidomain Peptides (MDPs) as scaffolds for T cell culture, activation, …

Ape-Gen20: Expanding Rapid Class I Peptide-Major Histocompatibility Complex Modeling To Post-Translational Modifications And Noncanonical Peptide Geometries, Romanos Fasoulis, Mauricio M Rigo, Gregory Lizée, Dinler A Antunes, Lydia E Kavraki

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The recognition of peptides bound to class I major histocompatibility complex (MHC-I) receptors by T-cell receptors (TCRs) is a determinant of triggering the adaptive immune response. While the exact molecular features that drive the TCR recognition are still unknown, studies have suggested that the geometry of the joint peptide–MHC (pMHC) structure plays an important role. As such, there is a definite need for methods and tools that accurately predict the structure of the peptide bound to the MHC-I receptor. In the past few years, many pMHC structural modeling tools have emerged that provide high-quality modeled structures in the general case. …

Toward Generalizable Machine Learning Models In Speech, Language, And Hearing Sciences: Estimating Sample Size And Reducing Overfitting, Hamzeh Ghasemzadeh, Robert E Hillman, Daryush D Mehta

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PURPOSE: Many studies using machine learning (ML) in speech, language, and hearing sciences rely upon cross-validations with single data splitting. This study's first purpose is to provide quantitative evidence that would incentivize researchers to instead use the more robust data splitting method of nested

METHOD: First, the significant impact of different cross-validations on ML outcomes was demonstrated using real-world clinical data. Then, Monte Carlo simulations were used to quantify the interactions among the employed cross-validation method, the discriminative power of features, the dimensionality of the feature space, the dimensionality of the model, and the sample size. Four different cross-validation methods …

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

Faculty, Staff and Student Publications

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

The Acceptance And Use Of Digital Technologies For Self-Reporting Medication Safety Events After Care Transitions To Home In Patients With Cancer: Survey Study, Yun Jiang, Misun Hwang, Youmin Cho, Christopher R Friese, Sarah T Hawley, Milisa Manojlovich, John C Krauss, Yang Gong

Faculty, Staff and Student Publications

BACKGROUND: Actively engaging patients with cancer and their families in monitoring and reporting medication safety events during care transitions is indispensable for achieving optimal patient safety outcomes. However, existing patient self-reporting systems often cannot address patients' various experiences and concerns regarding medication safety over time. In addition, these systems are usually not designed for patients' just-in-time reporting. There is a significant knowledge gap in understanding the nature, scope, and causes of medication safety events after patients' transition back home because of a lack of patient engagement in self-monitoring and reporting of safety events. The challenges for patients with cancer in …

Commentary On 2022 Guidelines On Clinical Trial Design In Cluster Headache And Further Suggestions, Ioana Medrea, Stewart J Tepper, Donliang Wang, Paul G Mathew, Mark Burish

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BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies.

MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment.

CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Final Results Of Urelumab, An Anti-Cd137 Agonist Monoclonal Antibody, In Combination With Cetuximab Or Nivolumab In Patients With Advanced Solid Tumors, Nikhil I Khushalani, Patrick A Ott, Robert L Ferris, Tina Cascone, Dirk Schadendorf, Dung T Le, Manish R Sharma, Fabrice Barlesi, William Sharfman, Jason J Luke, Ignacio Melero, Deanne Lathers, Jaclyn Neely, Satyendra Suryawanshi, Abanti Sanyal, James L Holloway, Rasika Suryawanshi, Scott Ely, Neil H Segal

Faculty, Staff and Student Publications

BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.

METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m

RESULTS: CA186-018: 66 patients received study treatment. The most frequent …

Rehabilitation Treatment Specification System For Voice Therapy: Application To Everyday Clinical Care, Jeremy Wolfberg, John Whyte, Patricia Doyle, Shirley Gherson, Jason Muise, Brian Petty, Carol Jorgensen Tolejano, Robert E Hillman, Tara Stadelman-Cohen, Jarrad H Van Stan

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PURPOSE: Rehabilitation intervention descriptions often do not explicitly identify active ingredients or how those ingredients lead to changes in patient functioning. The Rehabilitation Treatment Specification System (RTSS) provides guidance to identify the critical aspects of any rehabilitation therapy and supported the development of standardly named ingredients and targets in voice therapy (Rehabilitation Treatment Specification System for Voice Therapy [RTSS-Voice]). This study sought to test the content validity of the RTSS-Voice and determine if the RTSS-Voice can be used to identify commonalities and differences in treatment (criterion validity) across clinicians in everyday clinical practice.

METHOD: Five speech-language pathologists from different institutions …

Protein Biomarkers And Alternatively Methylated Cell-Free Dna Detect Early Stage Pancreatic Cancer, Roni Ben-Ami, Qiao-Li Wang, Jinming Zhang, Julianna G Supplee, Johannes F Fahrmann, Roni Lehmann-Werman, Lauren K Brais, Jonathan Nowak, Chen Yuan, Maureen Loftus, Ana Babic, Ehsan Irajizad, Tal Davidi, Aviad Zick, Ayala Hubert, Daniel Neiman, Sheina Piyanzin, Ofer Gal-Rosenberg, Amit Horn, Ruth Shemer, Benjamin Glaser, Natalia Boos, Kunal Jajoo, Linda Lee, Thomas E Clancy, Douglas A Rubinson, Kimmie Ng, John A Chabot, Fay Kastrinos, Michael Kluger, Andrew J Aguirre, Pasi A Jänne, Nabeel Bardeesy, Ben Stanger, Mark H O'Hara, Jacob Till, Anirban Maitra, Erica L Carpenter, Andrea J Bullock, Jeanine Genkinger, Samir M Hanash, Cloud P Paweletz, Yuval Dor, Brian M Wolpin

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Objective: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.

Design: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.

Results: Comparative methylome analysis identified nine loci that were differentially …

Safety, Tolerability, And Dose-Limiting Toxicity Of Lacosamide In Patients With Painful Chronic Pancreatitis: Protocol For A Phase 1 Clinical Trial To Determine Safety And Identify Side Effects, Evan L Fogel, Jeffrey J Easler, Ying Yuan, Dhiraj Yadav, Darwin L Conwell, Santhi Swaroop Vege, Samuel Y Han, Walter Park, Vanessa Patrick, Fletcher A White

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Background: Chronic abdominal pain is the hallmark symptom of chronic pancreatitis (CP), with 50% to 80% of patients seeking medical attention for pain control. Although several management options are available, outcomes are often disappointing, and opioids remain a mainstay of therapy. Opioid-induced hyperalgesia is a phenomenon resulting in dose escalation, which may occur partly because of the effects of opioids on voltage-gated sodium channels associated with pain. Preclinical observations demonstrate that the combination of an opioid and the antiseizure drug lacosamide diminishes opioid-induced hyperalgesia and improves pain control.

Objective: In this phase 1 trial, we aim to determine the safety, …

One Form And Two Functions: Mbd Of Setdb2 Is A Protein-Interacting Domain, Jujun Zhou, Taiping Chen, Xiaodong Cheng

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In this issue of Structure, Mahana et al.1 present their structural characterization of an annotated methyl-CpG-binding domain (MBD) from the histone H3 lysine 9 methyltransferase SETDB2. This study reveals that, rather than binding DNA as previously hypothesized, this domain instead interacts with a cystine-rich domain from C11orf46, highlighting its involvement in protein-protein interactions.

Deep Learning Model For Personalized Prediction Of Positive Mrsa Culture Using Time-Series Electronic Health Records, Masayuki Nigo, Laila Rasmy, Bingyu Mao, Bijun Sai Kannadath, Ziqian Xie, Degui Zhi

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Methicillin-resistant Staphylococcus aureus (MRSA) poses significant morbidity and mortality in hospitals. Rapid, accurate risk stratification of MRSA is crucial for optimizing antibiotic therapy. Our study introduced a deep learning model, PyTorch_EHR, which leverages electronic health record (EHR) time-series data, including wide-variety patient specific data, to predict MRSA culture positivity within two weeks. 8,164 MRSA and 22,393 non-MRSA patient events from Memorial Hermann Hospital System, Houston, Texas are used for model development. PyTorch_EHR outperforms logistic regression (LR) and light gradient boost machine (LGBM) models in accuracy (AUROC

Neuronal Npr-15 Modulates Molecular And Behavioral Immune Responses Via The Amphid Sensory Neuron-Intestinal Axis In C Elegans, Benson Otarigho, Anna Frances Butts, Alejandro Aballay

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The survival of hosts during infections relies on their ability to mount effective molecular and behavioral immune responses. Despite extensive research on these defense strategies in various species, including the model organism

Single-Cell Cd4 And Cd8 T-Cell Secretome Profiling Reveals Temporal And Niche Differences In Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy, Jessica L Root, Poonam N Desai, Christopher Ly, Bofei Wang, Fatima Zahra Jelloul, Jing Zhou, Sean Mackay, Mansour Alfayez, Jairo Matthews, Sherry Pierce, Patrick K Reville, Naval Daver, Hussein A Abbas

Faculty, Staff and Student Publications

UNLABELLED: Acute myeloid leukemia (AML) is a heterogeneous malignancy of the blood primarily treated with intensive chemotherapy. The allogeneic T-cell antileukemic activity via donor lymphocyte infusions and stem cell transplantation suggests a potential role for checkpoint blockade therapy in AML. While clinical trials employing these treatments have fallen short of expected results, a deeper exploration into the functional states of T cells in AML could bridge this knowledge gap. In this study, we analyzed the polyfunctional activity of T cells in a cohort of patients with relapsed/refractory (RelRef) AML treated on the clinical trial (ClinicalTrials.gov identifier: NCT02397720) of combination therapy …

Chimeric Oncolytic Adenovirus Evades Neutralizing Antibodies From Human Patients And Exhibits Enhanced Anti-Glioma Efficacy In Immunized Mice, Dong Ho Shin, Hong Jiang, Andrew G Gillard, Debora Kim, Xuejun Fan, Sanjay K Singh, Teresa T Nguyen, Sagar S Sohoni, Andres R Lopez-Rivas, Akhila Parthasarathy, Chibawanye I Ene, Joy Gumin, Frederick F Lang, Marta M Alonso, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent …

Inhibition Of Mer Proto-Oncogene Tyrosine Kinase By An Antisense Oligonucleotide Enhances Treatment Efficacy Of Immunoradiotherapy, Yun Hu, Alexey Revenko, Hampartsoum Barsoumian, Genevieve Bertolet, Natalie Wall Fowlkes, Hadi Maazi, Morgan Maureen Green, Kewen He, Duygu Sezen, Tiffany A Voss, Claudia S Kettlun Leyton, Fatemeh Masrorpour, Zahid Rafiq, Nahum Puebla-Osorio, Carola Leuschner, Robert Macleod, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

Background: The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice.

Methods: 344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 …

Immuno-Molecular Targeted Therapy Use And Survival Benefit In Patients With Stage Ivb Cervical Carcinoma In Commission On Cancer, Collin A Sitler, Chunqiao Tian, Chad A Hamilton, Michael T Richardson, John K Chan, Daniel S Kapp, Charles A Leath, Yovanni Casablanca, Christina Washington, Nicole P Chappell, Ann H Klopp, Craig D Shriver, Christopher M Tarney, Nicholas W Bateman, Thomas P Conrads, George Larry Maxwell, Neil T Phippen, Kathleen M Darcy

Faculty, Staff and Student Publications

PURPOSE: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials.

METHODS: Patients diagnosed with stage IVB cervical cancer during 2013-2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates.

RESULTS: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use …

Transcriptomic, Proteomic, And Genomic Mutational Fraction Differences Based On Hpv Status Observed In Patient-Derived Xenograft Models Of Penile Squamous Cell Carcinoma, Niki M Zacharias, Luis Segarra, Keiko Akagi, Natalie Wall Fowlkes, Huiqin Chen, Angelita Alaniz, Carolyn De La Cerda, Pedro Pesquera, Yuanxin Xi, Jing Wang, Jad Chahoud, Xin Lu, Priya Rao, Magaly Martinez-Ferrer, Curtis A Pettaway

Faculty, Staff and Student Publications

Simple Summary

Penile cancer is a rare but aggressive cancer. After it metastasizes, the median survival time is less than 12 months. The overall response rate to common first-line combination chemotherapy treatments is approximately 50%. There is an urgent need in advanced-penile-cancer treatment to find novel therapies that would generate better response rates than standard chemotherapy thus far and have less toxicity. Partially due to its rarity, there are few animal models and cell lines of penile cancer. We report on the generation of seven penile cancer animal models that were created by directly implanting human tumor tissue into immunocompromised …

Muc20 Regulated By Extrachromosomal Circular Dna Attenuates Proteasome Inhibitor Resistance Of Multiple Myeloma By Modulating Cuproptosis, Xiaobin Wang, Yingqing Shi, Hua Shi, Xiaoyu Liu, Aijun Liao, Zhuogang Liu, Robert Z Orlowski, Rui Zhang, Huihan Wang

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BACKGROUND: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation.

METHODS: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay.

RESULTS: …

Potential Protein Signatures For Recurrence Prediction Of Ischemic Stroke, Chengyi Zhang, Yang Liu, Huimin Zhu, Xinying Huang, Cang Guo, Si Cheng, Meng Yuan, Yong Jiang, Xia Meng, S Claiborne Johnston, Yongjun Wang, Wei-Na Jin, Fu-Dong Shi

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Background: Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence.

Methods and results: We conducted a nested case-control study using a hospital-based cohort from the Third China National Stroke Registry selecting 214 age- and sex-matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data-independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large-artery atherosclerosis (Causative Classification of Ischemic Stroke …

Unraveling The Intraday Variations In The Tear Fluid Proteome, Garrett Jones, Jeremy Altman, Saleh Ahmed, Tae Jin Lee, Wenbo Zhi, Shruti Sharma, Ashok Sharma

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PURPOSE: Tear fluid is a complex and dynamic biological fluid that plays essential roles in maintaining ocular homeostasis and protecting against the external environment. Owing to the small sample volume, studying the tear proteome is challenging. However, advances in high-resolution mass spectrometry have expanded tear proteome profiling, revealing >500 unique proteins. Tears are emerging as a noninvasive source of biomarkers for both ocular and systemic diseases; nevertheless, intraday variability of proteins in tear fluid remains questionable. This study investigates intraday variations in the tear fluid proteome to identify stable proteins that could act as candidate biomarkers.

METHODS: Tear samples from …

Eef1a2 Promotes Pten-Gsk3Β-Scf Complex-Dependent Degradation Of Aurora Kinase A And Is Inactivated In Breast Cancer, Warapen Treekitkarnmongkol, Luisa M Solis, Deivendran Sankaran, Mihai Gagea, Pankaj K Singh, Ragini Mistry, Tristian Nguyen, Kazuharu Kai, Jiajun Liu, Kaori Sasai, Yoshimi Jitsumori, Jianwen Liu, Norio Nagao, Fabio Stossi, Michael A Mancini, Ignacio I Wistuba, Alastair M Thompson, Jonathan M Lee, Juan Cadiñanos, Kwong-Kwok Wong, Catherine M Abbott, Aysegul A Sahin, Suyu Liu, Hiroshi Katayama, Subrata Sen

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The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin …